tbuckley/cabot-search huggingface dataset:
Association of Polycystic Ovary Syndrome With Pancreatic Cancer—Reply
Authors: Noah C. Peeri, Mengmeng Du
Journal: JAMA Oncology (2023)

In Reply We thank Levin and Meyer for their interest and comments regarding our case-control study of the association between polycystic ovary syndrome (PCOS) and pancreatic cancer risk.1 We appreciate the opportunity to respond.
Sparsentan: First Approval
Authors: Yahiya Y. Syed
Journal: Drugs (2023)

Sparsentan (FILSPARI™) is an oral, dual endothelin angiotensin receptor antagonist that is being developed by Travere Therapeutics for the treatment of immunoglobulin A (IgA) nephropathy and focal segmental glomerulosclerosis (FSGS). In February 2023, sparsentan received accelerated approval in the USA for reducing proteinuria in adults with primary IgA nephropathy who are at risk of rapid disease progression. This article summarizes the milestones in the development of sparsentan leading to this first approval for IgA nephropathy.
Mechano-Redox Control of Mac-1 De-Adhesion by PDI Promotes Directional Movement Under Flow
Authors: Alexander Dupuy, Camilo Aponte-Santamaría, Adva Yeheskel, Elinor Hortle, Stefan H. Oehlers, Frauke Gräter, Philip J. Hogg, Freda H. Passam, Joyce Chiu
Journal: Circulation Research (2023)

Neutrophil migration is critical to the initiation and resolution of inflammation. Macrophage-1 antigen (Mac-1; CD11b/CD18, αMβ2) is a leukocyte integrin essential for firm adhesion to endothelial ICAM-1 (intercellular adhesion molecule 1) and migration of neutrophils in the shear forces of the circulation. PDI (protein disulfide isomerase) has been reported to influence neutrophil adhesion and migration. We aimed to elucidate the molecular mechanism of PDI control of Mac-1 affinity for ICAM-1 during neutrophil migration under fluid shear.Neutrophils isolated from whole blood were perfused over microfluidic chips coated with ICAM-1. Colocalization of Mac-1 and PDI on neutrophils was visualized by fluorescently labeled antibodies and confocal microscopy. The redox state of Mac-1 disulfide bonds was mapped by differential cysteine alkylation and mass spectrometry. Wild-type or disulfide mutant Mac-1 was expressed recombinantly in Baby Hamster Kidney cells to measure ligand affinity. Mac-1 conformations were measured by conformation-specific antibodies and molecular dynamics simulations. Neutrophils crawling on immobilized ICAM-1 were measured in presence of oxidized or reduced PDI, and the effect of PDI inhibition using isoquercetin on neutrophil crawling on inflamed endothelial cells was examined. Migration indices in the X- and Y-direction were determined and the crawling speed was calculated.PDI colocalized with high-affinity Mac-1 at the trailing edge of stimulated neutrophils when crawling on ICAM-1 under fluid shear. PDI cleaved 2 allosteric disulfide bonds, C169-C176 and C224-C264, in the βI domain of the β2 subunit, and cleavage of the C224-C264 disulfide bond selectively controls Mac-1 disengagement from ICAM-1 under fluid shear. Molecular dynamics simulations and conformation-specific antibodies reveal that cleavage of the C224-C264 bond induces conformational change and mechanical stress in the βI domain. This allosterically alters the exposure of an αI domain epitope associated with a shift of Mac-1 to a lower-affinity state. These molecular events promote neutrophil motility in the direction of flow at high shear stress. Inhibition of PDI by isoquercetin reduces neutrophil migration in the direction of flow on endothelial cells during inflammation.Shear-dependent PDI cleavage of the neutrophil Mac-1 C224-C264 disulfide bond triggers Mac-1 de-adherence from ICAM-1 at the trailing edge of the cell and enables directional movement of neutrophils during inflammation.
Development of mouse models with restricted HLA-B∗57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury
Authors: Suryatheja Ananthula, Kirthiram Krishnaveni Sivakumar, Marco Cardone, Shan Su, Gregory Roderiquez, Hanan Abuzeineh, David E. Kleiner, Michael A. Norcross, Montserrat Puig
Journal: Journal of Allergy and Clinical Immunology (2023)

Flucloxacillin (FLX)-induced liver injury is immune-mediated and highly associated to HLA-B∗57:01 expression. Host factors leading to drug-induced liver injury are not yet well understood.Characterize in vivo immune mechanisms determining the development of CD8+ T cells reactive to FLX in animals expressing the risk human leukocyte antigen (HLA) allotype.HLA-B∗57:01 transgenic mice (Tg) or Tg strains with H2-KbDb knockout (Tg/KO) or H2-KbDb/PD-1 double knockout (Tg/DKO) were treated with drug and/or anti-CD4 antibody. Drug-induced liver injury was evaluated on the basis of liver enzyme and histologic changes at day 10 of treatment. FLX-reactive CD8+ T cells were characterized in vitro by release of effector molecules on drug restimulation, gene expression, and flow cytometry analysis, and functionality tested for hepatic cytotoxicity.CD8+ T-cell responses to FLX in Tg were dependent on both HLA and mouse major histocompatibility complex I presentation and in vivo priming. Eliminating H2-KbDb in Tg/KO to allow exclusive presentation of FLX by HLA resulted in a less robust drug-specific CD8+T-cell response unless CD4+ cells, including regulatory T cells, were depleted. Treatment of Tg/KO with anti-CD4 antibody and FLX led to subclinical liver inflammation associated with an increase in PD1+CD8+ T cells in the lymphoid organs and liver. Impaired PD-1 expression in Tg/DKO led to liver histopathologic and transcriptional alterations but without hepatic enzyme elevations. Moreover, effector lymphocytes accumulated in the liver and showed FLX-dependent hepatic cytotoxicity in vitro when tolerogenic liver cells were depleted.In our in vivo models, FLX primes CD8+ T cells to recognize drug presented by HLA-B∗57:01 and murine major histocompatibility complex I. HLA-B∗57:01-dependent CD8+ T-cell reaction to FLX is limited by the presence of CD4+ cells, presumably regulatory T cells, and PD-1 expression. Tolerogenic hepatic cells limit clinical disease through PD-L1 or additional unexplored mechanisms.
Fourteen-Year Outcome of Angle-Closure Prevention with Laser Iridotomy in the Zhongshan Angle-Closure Prevention Study
Authors: Yixiong Yuan, Wei Wang, Ruilin Xiong, Jian Zhang, Cong Li, Shaopeng Yang, David S. Friedman, Paul J. Foster, Mingguang He
Journal: Ophthalmology (2023)

This study aimed to evaluate the efficacy of laser peripheral iridotomy (LPI) prophylaxis for patients with primary angle-closure suspect (PACS) after 14 years and to identify risk factors for the conversion from PACS to primary angle closure (PAC).Extended follow-up of the Zhongshan Angle-Closure Prevention Study.Eight hundred eighty-nine Chinese patients 50 to 70 years of age with bilateral PACS.Each patient received LPI in 1 randomly selected eye, with the fellow untreated eye serving as a control. Because the risk of glaucoma was low and acute angle closure (AAC) occurred only rarely, the follow-up was extended to 14 years despite substantial benefits of LPI reported after the 6-year visit.Incidence of PAC, a composite end point including peripheral anterior synechiae, intraocular pressure (IOP) of > 24 mmHg, or AAC.During the 14 years, 390 LPI-treated eyes and 388 control eyes were lost to follow-up. A total of 33 LPI-treated eyes and 105 control eyes reached primary end points (P < 0.01). Within them, 1 LPI-treated eye and 5 control eyes progressed to AAC. Primary angle-closure glaucoma was found in 2 LPI-treated eyes and 4 control eyes. The hazard ratio for progression to PAC was 0.31 (95% confidence interval, 0.21-0.46) in LPI-treated eyes compared with control eyes. At the 14-year visit, LPI-treated eyes showed more severe nuclear cataract, higher IOP, and larger angle width and limbal anterior chamber depth (LACD) than control eyes. Higher IOP, shallower LACD, and greater central anterior chamber depth (CACD) were associated with an increased risk of end points developing in control eyes. In the treated group, eyes with higher IOP, shallower LACD, or less IOP elevation after the darkroom prone provocative test (DRPPT) were more likely to demonstrate PAC after LPI.Despite a two-third decrease in PAC occurrence after LPI, the cumulative risk of progression was relatively low in the community-based PACS population over 14 years. Apart from IOP, IOP elevation after DRPPT, CACD, and LACD, more risk factors are needed to achieve precise prediction of PAC occurrence and to guide clinical practice.The author(s) have no proprietary or commercial interest in any materials discussed in this article.
The global, regional, and national burden and its trends of inguinal, femoral, and abdominal hernia from 1990 to 2019: findings from the 2019 Global Burden of Disease Study – a cross-sectional study
Authors: Qiuyue Ma, Wenzhan Jing, Xiaoli Liu, Jue Liu, Min Liu, Jie Chen
Journal: International Journal of Surgery (2023)

Background: Inguinal, femoral, and abdominal hernia repairs are the most common surgical procedure worldwide. However, studies on hernia disease burden are notably limited, in both developed and low-income and middle-income countries (LMICs). We investigated temporal trends in the incidence and prevalence of inguinal, femoral, and abdominal hernias at global, regional, and national levels in 204 countries and territories from 1990 to 2019 using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). Materials and Methods: Annual incident cases, prevalent cases, age-standardized incidence rates (ASIRs), and age-standardized prevalence rates (ASPRs) of inguinal, femoral, and abdominal hernias between 1990 and 2019 were extracted from the GBD 2019 study and stratified by sex, age, and location. Percentage changes in incident cases and prevalent cases, and the estimated annual percentage changes of ASIRs and ASPRs were calculated to quantify the trends in the incidence and prevalence of inguinal, femoral, and abdominal hernias. Data analysis for the present study was conducted from 15 June 2022 to 15 July 2022. Results: Globally, there were 32.53 million [95% uncertainty interval (UI): 27.71–37.79] prevalent cases and 13.02 million (10.68–15.49) incident cases of inguinal, femoral, and abdominal hernias in 2019, which increased by 36.00% and 63.67%, respectively, compared with 1990. Eighty-six percent of the incident cases were males, the male-to-female ratio was 6 : 1, and most patients were aged 50–69 years. India (2.45 million), China (1.95 million), and Brazil (0.71 million) accounted for more than one-third (39%) of the incident cases worldwide. From 1990 to 2019, the ASIR and ASPR showed a decreasing trend worldwide, except in Central Sub-Saharan Africa, which had an increasing trend in ASIR and ASPR. Conclusion: The global incident cases and prevalent cases of inguinal, femoral, and abdominal hernias increased substantially from 1990 to 2019, with a heavier burden observed in males, older adults, and in LMICs such as India and China. In addition, the ASIR and ASPR increased substantially in Central Sub-Saharan Africa. More efforts are warranted for hernia management to reduce the burden of inguinal, femoral, and abdominal hernias, such as by providing safe hernia surgical treatment for males, older adults, and LMICs.
Does one-anastomosis gastric bypass provide better outcomes than sleeve gastrectomy in patients with BMI greater than 50? A systematic review and meta-analysis
Authors: Maryam Barzin, Amir Ebadinejad, Ali Aminian, Alireza Khalaj, Faranak Ghazy, Fatemeh Koohi, Farhad Hosseinpanah, Amirhossein Ramezani Ahmadi, Majid Valizadeh, Behnaz Abiri
Journal: International Journal of Surgery (2023)

In patients with BMI greater than 50, sleeve gastrectomy (SG) may not be adequate to treat obesity. To determine whether one-anastomosis gastric bypass (OAGB) can provide better outcomes compared with SG in patients with BMI greater than 50, a systematic review and meta-analysis was conducted, including a total of nine retrospective studies with a total of 2332 participants. There was a significant difference in the percentage of excess weight loss [weighted mean difference (WMD): 8.52; 95% CI: 5.81–11.22; P &lt;0.001) and percentage of total weight loss (WMD: 6.65; 95% CI: 5.05–8.24; P &lt;0.001). No significant differences were seen in operative time (WMD: 1.91; 95% CI: −11.24 to 15.07; P =0.77) and length of stay in hospital (WMD: −0.41; 95% CI: −1.18 to 0.37; P =0.30) between the two groups. There were no significant differences between OAGB with SG in Clavien–Dindo grades I–III [odds ratio (OR): 1.56; 95% CI: 0.80–3.05], or grade IV complications (OR: 0.72; 95% CI: 0.18–2.94). The meta-analysis on remission of type 2 diabetes indicated a comparable effect between SG and OAGB (OR: 0.77; 95% CI: 0.28–2.16). The OAGB group had a significantly higher rate of remission of hypertension compared with the SG group (OR: 1.63; 95% CI: 1.06–2.50). The findings of this meta-analysis suggest that the OAGB accomplished a higher percentage of total weight loss and percentage of excess weight loss at short-term and mid-term follow-up but, there was no major difference between the OAGB and SG operations in terms of perioperative outcomes, complications, and diabetes remission.
Inflammatory score predicts early hematoma expansion and poor outcomes in patients with intracerebral hemorrhage
Authors: Heling Chu, Chuyi Huang, Zaiying Zhou, Yuping Tang, Qiang Dong, Qihao Guo
Journal: International Journal of Surgery (2023)

Background: This study aimed to develop a prediction score named inflammatory score based on proper integration of several inflammatory markers and investigate whether it was associated with hematoma expansion and poor outcomes in patients with intracerebral hemorrhage (ICH). Methods: This study involved a consecutive series of spontaneous ICH patients of two cohorts admitted within 24 hours after symptom onset. Inflammatory score (0–9) was developed with the combination of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, systemic immune-inflammation index, lactate dehydrogenase, and C-reactive protein. The authors investigated the association between inflammatory score and hematoma expansion and poor outcomes by using univariate and multivariate logistic regression analyses. The optimal cutoff point of inflammatory score was determined by receiver operating characteristic analysis in the development cohort and then validated. Results: A total of 301 and 154 ICH patients were enrolled in the development and validation cohorts. Inflammatory score was significantly higher in patients with hematoma expansion and poor outcomes. The multivariate logistic regression analysis revealed inflammatory score was independently associated with hematoma expansion, secondary neurological deterioration within 48 hours, 30-day mortality, and 3-month poor modified Rankin scale (4–6). The diagnostic accuracy of inflammatory score exhibited by area under the curve showed numerically or statistically higher than most of the individual indicators. Moreover, inflammatory score greater than or equal to 5 was selected as the optimal cutoff point, which was further prospectively validated with high diagnostic accuracy. Conclusions: The inflammatory score is a reliable predictor for early hematoma expansion and short-term and long-term poor outcomes with good diagnostic accuracies in ICH patients.
The effect of vitamin B12 supplementation during pregnancy on infant growth and development in Nepal: a community-based, double-blind, randomised, placebo-controlled trial
Authors: Ram K Chandyo, Ingrid Kvestad, Manjeswori Ulak, Suman Ranjitkar, Mari Hysing, Merina Shrestha, Catherine Schwinger, Adrian McCann, Per M Ueland, Sudha Basnet, Laxman Shrestha, Tor A Strand
Journal: The Lancet (2023)
Psychotherapy for Chronic In- and Outpatients with Common Mental Disorders: The “Choose Change” Effectiveness Trial
Authors: Andrew T. Gloster, Elisa Haller, Jeanette Villanueva, Victoria Block, Charles Benoy, Andrea H. Meyer, Sandra Brogli, Veronika Kuhweide, Maria Karekla, Klaus Bader, Marc Walter, Undine Lang
Journal: Psychotherapy and Psychosomatics (2023)

Introduction: Treatment non-response occurs regularly, but psychotherapy is seldom examined for such patients. Existing studies targeted single diagnoses, were relatively small, and paid little attention to treatment under real-world conditions. Objective: The Choose Change trial tested whether psychotherapy was effective in treating chronic patients with treatment non-response in a transdiagnostic sample of common mental disorders across two variants of treatment delivery (inpatient and outpatient). Methods: The controlled nonrandomized effectiveness trial was conducted between May 2016 and May 2021. The study took place in two psychiatric clinics with N = 200 patients (n = 108 inpatients and n = 92 outpatients). Treatment variants were integrated inpatient care versus outpatient care based on acceptance and commitment therapy (ACT) for approximately 12 weeks. Therapists delivered individualized and non-manualized ACT. Main outcome measures were symptoms (Brief Symptom Checklist [BSCL]); well-being (Mental Health Continuum-Short Form [MHC-SF]), and functioning (WHO Disability Assessment Schedule [WHO-DAS]). Results: Both inpatients and outpatients showed decreases in symptomatology (i.e., BSCL: d = 0.68) and increases in well-being and functioning (MHC-SF: d = 0.60 and WHO-DAS: d = 0.70), with more improvement in the inpatients during treatment. Both groups maintained gains 1 year following treatment, and the groups did not significantly differ from each other at this timepoint. Psychological flexibility moderated impact of stress on outcomes. Conclusions: Psychotherapy as practiced under routine conditions is effective for a sample of patients with common mental disorders, a long history of treatment experience and burden of disease, in both inpatient and outpatient settings. Trial registration: This study was registered in the ISRCTN registry on May 20, 2016, with the registration number ISRCTN11209732.
Polar angle asymmetries in visual perception and neural architecture
Authors: Marc M. Himmelberg, Jonathan Winawer, Marisa Carrasco
Journal: Trends in Neurosciences (2023)

Human visual performance changes with visual field location. It is best at the center of gaze and declines with eccentricity, and also varies markedly with polar angle. These perceptual polar angle asymmetries are linked to asymmetries in the organization of the visual system. We review and integrate research quantifying how performance changes with visual field location and how this relates to neural organization at multiple stages of the visual system. We first briefly review how performance varies with eccentricity and the neural foundations of this effect. We then focus on perceptual polar angle asymmetries and their neural foundations. Characterizing perceptual and neural variations across and around the visual field contributes to our understanding of how the brain translates visual signals into neural representations which form the basis of visual perception.
Oncogenic role and target properties of the lysine-specific demethylase KDM1A in chronic lymphocytic leukemia
Authors: Qu Jiang, Johanna Stachelscheid, Johannes Bloehdorn, Alicja Pacholewska, Christoph Markus Aszyk, Francien Grotenhuijs, Tony Andreas Müller, Ozlem Onder, Prerana Wagle, Carmen Diana Herling, Maria Kleppe, Zhefang Wang, Kevin R. Coombes, Sandra Robrecht, Priya S. Dalvi, Bianca Andra Lungu, Petra Mayer, Lynne V. Abruzzo, Janine Altmüller, Birgit Sybille Gathof, Thorsten Persigehl, Kirsten Fischer, Billy Michael Chelliah Jebaraj, Hugh Young Rienhoff, Rupert C. Ecker, Yue Zhao, Christiane Josephine Bruns, Stephan Stilgenbauer, Kojo S. J. Elenitoba-Johnson, Michael Hallek, Michal R. Schweiger, Margarete Odenthal, Elena Vasyutina, Marco Herling
Journal: Blood (2023)

In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and that underlie its biological and clinical subsets. Characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. In efforts to establish effectors of the CLL-associated oncogene T-cell leukemia 1A (TCL1A), we identified here the lysine-specific histone demethylase KDM1A to interact with the TCL1A protein in B-cells in conjunction with an increased catalytic activity of KDM1A. We demonstrate that KDM1A is upregulated in malignant B-cells. Elevated KDM1A and associated gene expression signatures correlated with aggressive disease features and adverse clinical outcomes in a large prospective CLL trial cohort. Genetic Kdm1a knockdown (Kdm1a-KD) in Eμ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and pro-apoptotic pathways. Genetic KDM1A depletion also affected milieu components (T-, stromal, monocytic cells), resulting in significant reductions of their capacity to support CLL cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA-seq) and H3K4me3 marks (ChIP-seq) in Eµ-TCL1A vs. iKdm1aKD;Eµ-TCL1A mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL by altering histone methylation patterns with pronounced effects on defined cell death and motility pathways. Finally, pharmacologic KDM1A inhibition altered H3K4/9 target methylation and revealed marked anti-B-cell-leukemic synergisms. Overall, we established the pathogenic role and effector networks of KDM1A in CLL, namely via tumor-cell intrinsic mechanisms and impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.
Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution
Authors: Alexander Cox, Niklas Klümper, Johannes Stein, Danijel Sikic, Johannes Breyer, Christian Bolenz, Florian Roghmann, Philipp Erben, Ralph M. Wirtz, Bernd Wullich, Manuel Ritter, Michael Hölzel, Kristina Schwamborn, Thomas Horn, Jürgen Gschwend, Arndt Hartmann, Wilko Weichert, Franziska Erlmeier, Markus Eckstein
Journal: European Urology (2023)

Urothelial cancer (UC) care is moving toward precision oncology. For tumor biology-driven treatment of metastatic UC (mUC), molecular subtypes play a crucial role. However, it is not known whether subtypes change during metastatic evolution. To address this, we analyzed a UC progression cohort (N = 154 patients) with 138 matched primary tumors (PRIM) and synchronous or metachronous distant metastasis (MET) by immunohistochemistry, and mRNA sequencing in a subgroup of 20 matched pairs. Protein-based tumor cell subtypes and histomorphology remained stable during metastatic progression (concordance: 94%, 95% confidence interval [CI] 88-97%). In comparison, transcriptome-based molecular consensus subtypes exhibited higher heterogeneity between PRIM and MET (concordance: 45%, 95% CI 23-69%), with switches particularly occurring between luminal and stroma-rich tumors. Of note, all tumors classified as stroma rich showed luminal tumor cell differentiation. By an in-depth analysis, we found a negative correlation of luminal gene and protein expression with increasing desmoplastic stroma content, suggesting that luminal tumor cell differentiation of "stroma-rich tumors" is superimposed by gene expression signals stemming from the stromal compartment. Immunohistochemistry allows tumor cell subtyping into luminal, basal, or neuroendocrine classes that remain stable during metastatic progression. These findings expand our biological understanding of UC MET and have implications for future subtype-stratified clinical trials in patients with mUC. PATIENT SUMMARY: Urothelial carcinomas (UCs) occur in different appearances, the so-called molecular subtypes. These molecular subtypes will gain importance for the therapy of metastatic UCs in the future. We could demonstrate that the subtype remains stable during metastasis, which is highly relevant for future studies.